Sensitivity analysis on a physiologically-based pharmacokinetic and pharmacodynamic model for diisopropylfluorophosphate-induced toxicity in mice and rats
Sensitivity analysis on a physiologically-based pharmacokinetic and pharmacodynamic model for diisopropylfluorophosphate-induced toxicity in mice and rats
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DOI：
10.1080/15376510903300335
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发表时间：
2009-01-01
影响因子：
3.2
通讯作者：
Seng, Kok -Yong
中科院分区：
文献类型：
--
作者：
Chen, Kaizhen;Teo, Shiyi;Seng, Kok -Yong
建立了一种基于生理学的药代动力学和药效学（PBPK/PD）模型，用于研究氟磷酸二异丙酯（DFP）对小鼠和大鼠乙酰胆碱酯酶（AChE）活性的影响。该模型考虑到涉及许多参数的相对复杂的相互作用，其中一些参数可能是不确定的和/或高度可变的，特别是那些表征DFP中毒后AChE活性的参数。本研究的主要目的是确定参数，最有助于对数据的模型优化的AChE动力学的变异性。为了这个目的，合成（K-syn）和降解（K-deg）的乙酰胆碱酯酶，再生（K-reg）和老化（K-age）的抑制乙酰胆碱酯酶的活性在小鼠和大鼠静脉血和脑的变异性的速率常数的变异性的影响，首先计算的全球敏感性分析。接下来，通过优化K-syn、K-deg、K-reg和K-age的值来校准小鼠PBPK/PD模型。此后，放大的DFP诱导的AChE活性进行从小鼠到大鼠。通过比较静脉血和脑AChE活性的时间过程从Monte Carlo分析在体内获得的那些进行验证的大鼠模型。敏感性分析表明，K-reg和K-syn是最有影响力的AChE活性在较短和较长的时间内，DFP挑战后，分别。从小鼠到大鼠的乙酰胆碱酯酶动力学的规模也是成功的，证明了预测的95（第）百分位数的置信区间和实验数据之间的显着重叠。
A physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was recently developed to study the effect of diisopropylfluorophosphate (DFP) on acetylcholinesterase (AChE) activity in mouse and rat. That model takes into account relatively complex interactions involving many parameters, some of which may be uncertain and/or highly variable, especially those characterizing AChE activity after DFP intoxication. The primary objective of this study was to identify parameters that contribute most to the variability of AChE dynamics for model optimization against data. For this purpose, the influence of the variability of the rate constants for synthesis (K-syn) and degradation (K-deg) of AChE, and regeneration (K-reg) and aging (K-age) of inhibited AChE on the variability of AChE activity in mice and rat venous blood and brain was first calculated by a global sensitivity analysis. Next, the mouse PBPK/PD model was calibrated by optimizing the values of K-syn, K-deg, K-reg and K-age. Thereafter, scale-up of the DFP-induced AChE activity was performed from mouse to rat. Validation of the rat model was performed by comparing the time course of venous blood and brain AChE activities from a Monte Carlo analysis to those obtained in vivo. Sensitivity analysis on the verified models showed that K-reg and K-syn were the most influential factors of AChE activity at shorter and longer durations, respectively, after DFP challenge. Scale-up of the AChE dynamics from mouse to rat was also successful, as evidenced by significant overlapping between the predicted 95(th) percentile confidence intervals and the experimental data.